Project Summary The majority of the US population that suffers from temporomandibular joint (TMJ) degeneration and osteoarthritis (TMJ-OA) are females between 45 and 65 years old. Prevalence of TMJ-OA in this population suggests that estrogen loss plays a role in the disease pathogenesis. Previous evidence from our lab suggests that estrogen through estrogen receptor alpha (ER?) protects the TMJ from degeneration by promoting Col2 and proteoglycan production. Further, we have preliminary evidence indicating that estrogen-ER? inhibits Wnt pathway signaling. These findings suggest that estrogen signaling promotes chondrogenesis via ER? by mediating the canonical Wnt pathway. The objective of this proposal is to investigate the role of ER? signaling on mandibular condylar cartilage matrix production and TMJ homeostasis. The proposed work comprises two aims: AIM 1: Evaluate the role of estrogen via ER? on collagen type II (Col2) production. We hypothesize that estrogen promotes Col2 transcription via ER? by inhibiting canonical Wnt signaling. To confirm the effects of estrogen-ER? on chondrogenesis, reporter mice will be utilized to examine upregulation of Col2 and downregulation of Wnt signaling with estrogen and an ER? agonist. Then, the ability of estrogen-ER? to promote chondrogenesis by inhibiting Wnt signaling will be determined by activating the Wnt pathway in WT and ER?KO mice in an ovariectomy-estrogen replacement model. AIM 2: Determine the effects of ER? deficiency on TMJ degeneration and correlate to resulting compressive properties and masticatory function. We hypothesize that ER?KO mice will exhibit accelerated age-related TMJ degeneration which will correspond to a decrease in compressive modulus, fixed charge density, and bite force compared to WT controls. Changes in matrix composition will be correlated to alterations in compressive properties and masticatory function. The results from this proposed research will provide evidence of the sex predilection of TMJ degeneration and provide therapeutic targets (e.g. ER? agonist) to delay degeneration. Through this work, we aim to enhance the understanding of estrogen?s role in TMJ condylar cartilage chondrogenesis and homeostasis. Also, the development of TMJ condylar cartilage structure/function relationships will be beneficial for the development of regenerative therapies to combat TMJ degeneration.